5-tertiaryaminoalkylidene dibenzocycloheptadiene compounds, and salts thereof



United States Patent 3,384,663 S-TERTIARYAMINOALKYLIDENE DIBENZOCY-CLOHEPTADIENE COMPOUNDS, AND SALTS THEREOF Grald Rey-Bellet ad HansSpiegelberg, Basel, Switzerland, assignors to Hotfmann-La Roche Inc.,Nutley, N.J., a corporation of New Jersey No Drawing. Originalapplication Mar. 27, 1959, Ser. No, 802,298. Divided and thisapplication Oct. 27, 1967, Ser. No. 678,552

13 Claims. (Cl. 260-570.8)

Cross reference to related applications This application is a divisionof Ser. No. 802,298, filed Mar. 27, 1959.

Detailed description of the invention This invention relates to novelchemical products and to novel processes for making the same.

In one comprehensive embodiment, the product aspect of the inventionrelates to compounds having the formula Y 1 wherein Y represents adivalent radical selected from the group consisting of and \ CH(CHa)nBand B represents a tertiary amino radical, R is hydrogen, bromine orchlorine and n represents an integer from 2 to -6, inclusive;

to acid addition salts with pharmaceutically acceptable acids of saidcompounds having the above general Formula I; and to quaternary saltswith pharmaceutically acceptable quaternizing agents of said compoundshaving the above general Formula I. Exemplary, but not limitative, ofpharmaceutically acceptable acids are inorganic acids (e.g.,hydrochloric, hydrobromic, sulfuric and phosphoric acids) and organicacids (e.g., acetic, oxalic, citric, lactic, tartaric andethane-sulfonic acids). Exemplary,

3,384,663 Patented May 21, 1968 but not limitative, of pharmaceuticallyacceptable quaternlzing agents are esters of lower alkanols andaralkanols with mineral acids (e.g., methyl bromide, ethyl iodide,dimethylsulfate, benzyl bromide), esters of lower alkanols andaralkanols with sulfonic acids (e.g., ethyl p-toluenesulfonate), and thelike. Exemplary, but not lrmitative, of tertiary amino radicalsrepresented by the symbol B are di(lower alkyl) amino (e.g.,dimethylammo, diethylamino and the like), piperidino, morphollIlO,pyrrolidino, and the like.

The novel products referred to in the preceding paragraph--i.e., thecompounds of Formula I and the acid addition salts and quaternarysalts-are characterized by manifold activity upon the central nervoussystem, and are useful as pharmacological and medicinal agents, moreparticularly as narcosis-potentiating, adrenolytic, sedative,antihistaminic, antiemetic, antipyretic and hypothermic agents.

The novel products referred to above can be made, by processes describedbelow, from dibenzo[a,e]cyclohepta- [1,5]dien-5-one, Formula II below:

wherein R is as defined above.

(The above Formula II is marked to indicate the system of numbering andlettering employed in the nomenclatures recited in the presentspecification.) The ketone of Formula II can be made by methods knownper se. For example, these ketones can be made by reduction of thecorrespondingly substituted benzalphthalides and ring closure of thethus obtained dibenzyl-o-carboxylic acids.

In another comprehensive embodiment, a process aspect of the inventionprovides an overall method of making compounds included under Formula Iabove.

In this aspect, the invention relates to a process which comprisescondensing a ketone having Formula II with an organometallic compoundhaving the formula and hydrolyzing the metal-containing condensationproduct obtained, thereby producing a tertiary alcohol having theformula CHn(CHz)nB IV wherein the symbols n, R and B have the samemeaning defined above in connection with Formula I,

treating said tertiary alcohol with a dehydrating agent, therebyproducing a semicyclically unsaturated compound having the formulaiimonnne v wherein the symbols n, R and B have the same meaning definedabove in connection with Formula I,

and catalytically hydrogenating said semicyclically unsaturatedcompound, thereby producing a compound having the formula It will beappreciated from the foregoing that, in addition to the ketone startingmaterial [i.e., (11)], it is also necessary to have available thestarting material (III). The latter can be made by methods known per se.One preferred process of the invention employs, as a specific embodimentof reactant (III), a Grignard reagent made from a di(lower alkyl)amin(lower alkyl) halide. Such Grignard reagents can be made by directreaction of metallic magnesium with an ethereal solution of thedialkylaminoalkyl halide referred to above. In such cases, it ispreferred to employ a highly active form of magnesium. Conveniently, onecan employ finely divided copper-magnesium alloy, e.g., that disclosedby Gilman, Recueil des Trav. Chim. des Pays Has, 47, 19 (1928), thereaction being facilitated by addition of a suitable lower alkyl halide,e.g., methyl iodide, ethyl bromide or the like.

The first stage of the comprehensive process embodiment referred toabove comprises condensing the ketone reactant (II) with theorganometallic reactant (III) and hydrolyzing the condensation product.In a preferred mode of execution, the ketone reactant, either in solidfinely pulverized form or in an inert organic liquid, e.g., absoluteether, benzene, tetrahydrofuran or the like, is added to the Grignardreagent of the tertiary amino alkyl halide in the same or a similarinert organic liquid. Upon completion of the condensation reaction, themetal-containing condensation product is subjected to hydrolyticdecomposition. It is especially advantageous to decompose themetal-containing condensation product under practically neutralconditions, e.g., by hydrolysis in aqueous ammonium chloride solution.In this way, the tertiary alcohol product obtained, i.e., (IV), isobtained directly in free form, and can be separated from theby-products of the reaction and isolated by treatment with suitablewater-immiscible organic solvents, e.g., ether, ethyl acetate,chloroform, methylene chloride or the like.

In a second state, which can be elfected optionally, the tertiaryalcohol product obtained in the first stage, i.e., a S-basicallysubstituted dibenzo[a,e]cyclohepta[1,5]dien- 5-01, can be subjected to adehydration step. The dehydration is effected especially advantageouslyby heating with alcoholic hydrogen chloride. It can also be effected,however, with other conventional dehydrating agents, such as phosphorusoxychloride, sulfuric acid, zinc chloride, potassium bisulfate and thelike.

In a further optional reaction stage, the semicyclically unsaturatedcompound obtained by the dehydration reaction above referred to, i.e., acompound of Formula V above can be subjected to a step of catalytichydrogenation. The hydrogenation is most conveniently effected in thepresence of Raney nickel.

In one preferred embodiment of its product aspect, the inventionprovides compounds represented by the formula HO CH(CH2)nB VII whereinthe symbols n and B have the same meaning defined above in connectionwith Formula I,

. 4. and nuclear halogen (for example, chlorine and bromine)substitution derivatives thereof wherein a halo substituent is solelypresent in a nuclear fi- (i.e., 2-, 3-, 7- or 8-) position, and acidaddition salts of each of the foregoing with pharmaceutically acceptableacids.

In another preferred embodiment, the invention provides compounds havingthe formula II CH (OHQDB VIII wherein the symbols n and B have the samemeaning defined above in connection with general Formula I,

and nuclear halogen (for example, chlorine and bromine) substitutionderivatives thereof wherein a halo substituent is solely present in anuclear ,8- (i.e., 2-, 3-, 7- or 8-) position, and acid addition saltsof each of the foregoing with pharmaceutically acceptable acids.

In still another preferred embodiment, the invention provides compoundshaving the formula wherein the symbols n and B have the same meaningdefined above in connection with general Formula I,

and nuclear halogen (for example, chlorine and bromine) substitutionderivatives thereof wherein a halo substituent is solely present in anuclear 18- (i.e., 2-, 3-, 7- or 8-) position, and acid addition saltsof each of the foregoing with pharmaceutically acceptable acids.

The invention is further disclosed in the following examples, which areillustrative but not limitative thereof.

Example 1 In a one-liter, three-neck flask, fitted with a stirrer,dropping funnel and condenser, 2.5 g. of Gilman alloy (op. cit. supra)was covered with 10 cc. of dry ether and reacted with 0.5 cc. of methyliodide.

After the vigorous reaction subsided somewhat, 7.5 g. of magnesiumshavings were added in one portion and a solution of 40 g. of freshlydistilled w-dimethylaminopropyl chloride in 180 cc. of dry ether wasadded dropwise over a period of one hour. The reaction mixture washeated under reflux at 40 C. for five hours longer, and then was stirredovernight at room temperature.

On the following day, a solution of 21.2 g. of dibenzo[a,e]-cyclohepta[1,5]dien-5-one in 400 cc. of dry ether was added littleby little, while stirring. The whole was then stirred 20 hours longer at20-25 C. Then the reaction mixture was cooled with ice water and mixedwith a cold saturated ammonium chloride solution. The organic layer wasseparated, the aqueous phase was extracted twice with cc. portions ofether, and the combined ether layers were dried over sodium sulfate andevaporated. The residue, upon recrystallization from high boilingpetroleum ether, yielded colorless crystals of S-hydroxy 5 (wdimethylaminopropyl)dibenzo[a,e]cyclohepta[l,5]diene, melting at l18119C.

20 g. of S-hydroxy-S-(w-dimethylaminopropyl-dibenzo[a,e]cyclohepta[1,5]diene obtained was dissolved in 200 cc. of absolutealcohol, mixed with 20 cc. of 30 percent alcoholic hydrogen chloridesolution, and the mixture was refluxed for 1 /2 hours. The alcohol wasevaporated under diminished pressure and the residue was recrystallizedfrom alcohol-ether. The 5-(w-dimethylaminopropylidene)-dibenzo[a,e]cyclohepta[l,5]diene hydrochloride (amitriptylinehydrochloride) thus obtained formed colorless, water-soluble crystals,of MP. l94-195 C.

16 g. of 5 (w dirnethylaminopropylidene) dibenzo[a,e])cyclohepta[l,5]diene hydrochloride was dissolved in a little waterand the solution was made alkaline with aqueous sodium hydroxidesolution, whereupon the free base precipitated. The latter was extractedby shaking with ethyl acetate, the extract was dried and the solvent wasdistilled off. The oily free base remained, and was dissolved in 100 cc.of alcohol and then hydrogenated in the presence of Raney nickel at 6070C., under a hydrogen pressure of 30 atmospheres gauge. Upon filtrationof the reaction mixture, evaporation of the alcohol and distillation ofthe residue, there was obtained S-(w-dlmethylaminopropyl) -dlbenzo a,e]cyclohepta[ 1,5 diene as a colorless oil, B.P 145 C./0.1 mm. Hg. Thehydrochloride, upon recrystallization from alcohol-ether, melted at181-182 C.

Example 2 In a one-liter, three-neck flask fitted with a stirrer,dropping funnel and condenser, 2.5 g. of Gilman alloy was covered withcc. of dry ether and reacted with 0.5 cc. of methyl iodide.

After the vigorous reaction had subsided somewhat, 7.5 g. of magnesiumshavings were added in a single portion, and a solution of 40 g. offreshly distilled w-dimethylaminopropyl chloride in 180 cc. of dry etherwas added dropwise over a period of an hour. The reaction mixture wasrefluxed at 40 C. for five hours longer and then was stirred overnightat room temperature.

On the following day, a solution of 24.75 g. of 3-chlorodibenzo[a,elcyclohepta[l,5]dien5-ones in 400 cc. of dry ether wasslowly added, dropwise, while stirring. The whole was stirred for anadditional period of hours at 2025 C. Then the reaction mixture wascooled with ice water and mixed with a cold saturated ammonium chloridesolution. The organic layer was separated, the aqueous layer wasextracted twice with 100 cc. portions of ether, and the combinedethereal portions were dried over sodium sulfate and evaporated. Theresidue, upon recrystallization from high boiling petroleum ether,yielded colorless crystals of3-chloro-5-hydroxy-5-(w-dimethylaminopropyl)dibenzo[a,e]cyclohepta[1,5]diene, melting at l27-128 C.

10 g. of3-chloro-5-hydroxy-5-(w-dirnethylaminopropyl)-dibenzo[a,e]cyclohepta[1,5]dienethus obtained was dissolved in 100 cc. of absolute alcohol, mixed with10 cc. of 30% alcoholic hydrogen chloride solution, and heated at refluxfor two hours. The residue obtained, upon evaporation of the alcoholunder diminished pressure, was recrystallized from alcohol-ether. The3-chloro-5-(w-dimethylaminopropylidene) dibenzo[a,e]cyclohepta[1,5]diene hydrochloride thus obtained formed colorless, Water-solublecrystals, of M.P. 2102l2 C.

The starting material, 3-chloro-dibenzo[a,e] cyclohepta-[l,5]dien-5-one, can be prepared as follows:

100 g. of phthalic anhydride, 137 g. of 4-chlorophenylacetic acid and2.6 g. of freshly molten sodium acetate were mixed well in a 500 cc.round bottom flask, and the mixture was quickly heated in a sand bath to230 C., and then was slowly heated over a period of two hours to 240 C.,and finally was kept at 240 C. until water no longer distilled off. Themixture was cooled, whereupon it became solid. It was thenrecrystallized from a large quantity of absolute alcohol, whereupon4-chlorobenzal phthalide, of M.P. l5l152 C., was obtained.

A mixture of 51.3 g. of 4-chlorobenzal phthalide, 100 cc. of hydriodicacid (d=1.7) and 18 g. of red phosphorus was refluxed for 15 hours. Thereaction mixture was cooled and then was mixed with sufficient water andmethylene chloride that all the material, with the exception of the redphosphorus, went into solution. The methylene chloride layer wasseparated, washed with water, and was then extracted several times with5% aqueous sodium carbonate solution. Upon acidification of the combinedaqueous phases with hydrochloric acid, 4-chlorodibenzyl-2-carboxylicacid precipitated, and the latter was extracted with methylene chloride.Upon drying and evap- 6 oration of the methylene chloride solution, theresidual 4-chloro-dibenzyl-2'-carboxylic acid obtained wasrecrystallized from high boiling petroleum ether and then had a meltingpoint of 129130 C.

To 270 g. of well stirred polyphosphoric acid, heated to 170 C., wasadded portionwise, over a period of two hours, 57.6 g. of4-chloro-dibenzyl-2'-carboxylic acid. The reaction mixture was stirredat 170 C. for three hours longer, then was poured onto ice and thereaction product was extracted by shaking with ether. The etherealsolution was washed with aqueous sodium carbonate and solution, thenwith water, then was dried over sodium sulfate and evaporated. Theproduct, 3-chloro-dibenzo- [a,e]-cyclohepta[1,5]dien-5-one, Was purifiedby distillation (B.P. -155 C./0.05 mm. Hg) and then by recrystallizationfrom high boiling petroleum ether, whereupon it had M.P. 6465 C.

Example 3 In a two-liter, three-neck flask fitted with stirrer, droppinfunnel atnd condenser, 5 g. of Gilman alloy were covered with 20 ml. ofdry ether and reacted with 1 cc. of methyl iodide.

After the vigorous reaction had subsided somewhat, 15 g. of magnesiumshavings were added in a single portion and a solution of 70 g. offreshly distilled w-piperidinopropyl chloride in 360 cc. of dry etherwas added dropwise over a period of an hour. The reaction mixture wasrefluxed at 40 C. for an additional period of six hours and then stirredovernight at room temperature.

On the following day, a solution of 42.4 g. of dibenzo-[a,e]-cyclohepta[1,5]dien-5-one in 600 cc. of dry ether was slowly addeddropwise. The Whole was then stirred for an additional period of 18hours at 20-25 C. Then, the reaction mixture was cooled with ice water,mixed with a cold saturated ammonium chloride solution and filtered. Themain fraction of the reaction product was extracted with methylenechloride from the solid residue and a little additional substance wasobtained by concentrating the organic layer.

After recrystallization from absolute ethanol, the 5- hydroxy 5 (wpiperidinopropyl) dibenzo[a,e]cyclohepta[1,5]diene was obtained ascolorless crystals melting at 167-168".

27 g. of the thus obtained5-hydroxy-5-(w-piperidinopropyl)-dibenzo[a,e]cyclohepta[1,5]diene weredissolved in 270 cc. of absolute alcohol, mixed with 27 cc. of 30%alcoholic hydrogen chloride solution, and refluxed for three hours on asteam bath. The residue obtained, upon evaporation of the alcohol underdiminished pressure was recrystallized from alcohol-ether. The productthus obtained,(w-piperidinopropylidene) dibenzo[a,e]cyclohepta[l,5]diene hydrochloride, melted at 213-214 C.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformula and acid addition salts thereof with pharmaceutically acceptableacids and quaternary salts thereof; wherein Y is H oHnoHmB R ishydrogen, bromine or chlorine; B is di(lower alkyl) amino; and n is aninteger from 2 to 6, inclusive.

2. A compound as in claim 1 wherein n is 2.

3. A compound as in claim 2. wherein R is hydrogen.

4. A compound as in claim 3 which isS-(w-dimethylaminopropylidene)-dibenz[a,e]cyclohepta[1,5]diene.

5. A compound as in claim 3 which is S-(w-dimethyI-aminopropylidene)-dibenzo[a,e]cyc1ohepta[1,5]diene hydrochloride.

6. A compound as in claim 3 which is S-(w-dimethyI-aminopropyl)-dibenzo[a,e]cyclohepta[1,5]diene.

7. A compound as in claim 3 which is S-(w-dimethyI- aminopropyl)dibenzo[a,e]cyclohepta[l,5]diene hydrochloride.

8. A compound as in claim 2 wherein R is bromine or chlorine and is in aB-nuclear position.

9. A compound as in claim 8 which is3-ch1oro-5-(wdimethylaminopropylidene) dibenzo[a,e]cyclohepta[1,5]diene.

10. A compound as in claim 8 which is 3-chloro-5-(w-dimethylaminopropylidene) dibenzo[a,e]cyclohepta- 1,5] dienehydrochloride.

11. A compound selected from the group consisting of compounds of theformula HO CH2(OH2)DB and acid addition salts thereof withpharmaceutically acceptable acids and quaternary salts thereof; whereinR is hydrogen, bromine or chlorine; B is di(lower alkyl)amino; and n isan integer from 2 to 6, inclusive.

12. A compound as in claim 11 which is S-hydroxy-S- (wdimethylaminopropyl) dibenzo[a,e]cyc1ohepta[1,5] diene.

13. A compound as in claim 11 which is 3-chloro-5- hydroxy 5 (wdimethylarninopropyl) dibenzo[a,e] cy clohepta[1,5]diene.

References Cited FOREIGN PATENTS 858,186 1/1961 Great Britain.

CHARLES B. PARKER, Primary Examiner.

ROBERT V. HINES, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,384,663 May 21 1968 Gerald Rey-Bellet et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

In the heading to the printed specification, between lines 10 and 11,insert Claims priority, application Switzerland, Apr. 3, 1958 57,958Column 1, line 23, "tertiarylaminopropyl" shoud read tertiaryaminopropylline 23, "tertiaryaminopylidene" should read tertiaryaminopropylideneColumn 4, line 65, "dimethylaminopropyl-" should readdimethylaminopropyl)- Column 5, line 1, "[a,e])cyc1ohepta" should read[a,e] cyclohepta Column 6, line 21 "pin" should read ping line 21 "atnd"should read and line 52 (mpiperidino" should read H 5(wpiperidino lines71 to 75, the formula should appear as shown below:

Signed and sealed this 11th day of November 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

